Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

Kerry J. Ressler (), Kristina B. Mercer, Bekh Bradley, Tanja Jovanovic, Amy Mahan, Kimberly Kerley, Seth D. Norrholm, Varun Kilaru, Alicia K. Smith, Amanda J. Myers, Manuel Ramirez, Anzhelika Engel, Sayamwong E. Hammack, Donna Toufexis, Karen M. Braas, Elisabeth B. Binder and Victor May
Additional contact information
Kerry J. Ressler: Howard Hughes Medical Institute
Kristina B. Mercer: Howard Hughes Medical Institute
Bekh Bradley: Emory University School of Medicine
Tanja Jovanovic: Emory University School of Medicine
Amy Mahan: Yerkes National Primate Research Center
Kimberly Kerley: Howard Hughes Medical Institute
Seth D. Norrholm: Emory University School of Medicine
Varun Kilaru: Emory University School of Medicine
Alicia K. Smith: Emory University School of Medicine
Amanda J. Myers: University of Miami, Miller School of Medicine
Manuel Ramirez: University of Miami, Miller School of Medicine
Anzhelika Engel: University of Miami, Miller School of Medicine
Sayamwong E. Hammack: University of Vermont
Donna Toufexis: Yerkes National Primate Research Center
Karen M. Braas: University of Vermont College of Medicine
Elisabeth B. Binder: Emory University School of Medicine
Victor May: University of Vermont College of Medicine

Nature, 2011, vol. 470, issue 7335, 492-497

Abstract: Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP–PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP–PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.

Date: 2011
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DOI: 10.1038/nature09856

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